Biomedical subjects

N T Zervas

Publications and source records attributed to N T Zervas.

At least 55 records · Page 3Linked to original sources

PubMed1991

Somatostatin regulation of glycoprotein hormone and free subunit secretion in clinically nonfunctioning and somatotroph adenomas in vitro.

There is increasing evidence that clinically nonfunctioning pituitary tumors produce and secrete glycoprotein hormone and/or free alpha- and beta-subunits. In addition, hypersecretion of free alpha-subunit occurs in up to 37% of patients with somatotroph adenomas. An understanding of glycoprotein hormone regulation is important in developing effective therapeutic strategies for patients with tumors associated with intact glycoprotein hormone and free subunit hypersecretion. We investigated glycoprotein hormone and free subunit secretion by somatostatin in primary dispersed cultures of pituitary tumor cells from 23 patients with pituitary adenomas. Fifteen tumors from patients with clinically nonfunctioning adenomas (group 1) and 8 tumors from patients with somatotroph adenomas and cosecretion of alpha-subunit (group 2) were studied. Cultures were incubated with control or somatostatin-supplemented media for 24 h. Media samples from group 1 tumors were assayed for intact glycoprotein hormones and free alpha- and beta-subunits secretion levels, while media samples from group 2 cultures were assayed for alpha-subunit and GH secretion levels. Significant (P less than 0.05-0.001) inhibition of secretion of 1 or more intact hormones and/or free subunits was found in 10 of the 15 group 1 tumors. SRIF[10(-7) M] suppressed intact gonadotropin secretion in 60% of FSH-producing tumors and 30% of LH-producing tumors. Media concentrations of FSH beta and LH beta were decreased in 31% and 50% of group 1 tumors, respectively, following somatostatin treatment in those tumors which secreted free beta-subunits. alpha-Subunit was secreted by 12 of the 15 tumors, but significant (P less than 0.02-0.01) inhibition by somatostatin was observed in only 2 tumors. In contrast, significant (P less than 0.05-0.001) inhibition of alpha-subunit in the somatotroph adenomas was found in 6 of the 8 tumors. Significant decreases in alpha-subunit were observed only in those tumors where GH was also significantly inhibited by somatostatin. We conclude that 1) somatostatin inhibits intact glycoprotein or free subunit secretion in the majority of clinically nonfunctioning pituitary tumors in vitro and 2) alpha-subunit secretion is suppressed in 17% and 69% of clinically nonfunctioning and somatotroph adenomas, respectively, consistent with a differential regulation of alpha-subunit by somatostatin in these two tumor types.

Adenoma↗

PubMed1991

Application of the 1-microsecond pulsed-dye laser to the treatment of experimental cerebral vasospasm.

Laser energy of 480 nm was applied in 1-microsecond pulses varying between 2.2 and 10 mJ to in vitro and in vivo models of cerebral vasospasm. First, the pulsed-dye laser was applied intravascularly via a 320-microns fiber to basilar artery segments from six dogs. The segments were mounted in a vessel-perfusion apparatus and constricted to, on average, 70% of resting diameter by superfusion with dog hemolysate. Immediate increase in basilar artery diameter occurred to a mean of 83% of control. In a second model, the basilar artery was exposed transclivally in the rabbit. In three normal animals, superfusion of the artery with rabbit hemolysate resulted in a reduction of mean vessel diameter to 81% of control. Following extravascular application of the laser, vessels returned to an average of 106% of the resting state. In six rabbits, the basilar artery was constricted by two intracisternal injections of autologous blood. 3 days apart. Two to 4 days after the second injection, the basilar artery was exposed. Extravascular laser treatment from a quartz fiber placed perpendicular to the vessel adventitia resulted in an immediate 53% average increase in caliber to an estimated 107% of control. No reconstriction was observed over a period of up to 5 hours. Morphologically, damage to the arterial wall was slight. This preliminary investigation suggests that the 1-microsecond pulsed-dye laser may be of benefit in the treatment of cerebral vasospasm.

Animals↗

PubMed1991

Treatment of vasospasm with a 480-nm pulsed-dye laser.

Laser energy at a wavelength of 480 nm was applied in 1-microseconds pulses of 3 to 10 mJ to two models of vasospasm. Rabbit common carotid arteries (CCA's) were constricted chronically by the application of human blood within a silicone sheath. Peak vasospasm developed 24 to 48 hours later, and persisted for up to 6 days. Endovascular laser treatment was delivered to 40 CCA's via a 200-microns diameter silica quartz fiber introduced through the femoral artery. The CCA caliber increased from 60% of the pre-vasospasm control diameter to a minimum post-laser diameter of 83% of control. No instances of laser-induced perforation or of arterial thrombosis were observed for up to 60 days after treatment. Prophylactic laser application to nine normal vessels was able to attenuate the development of vasospasm if blood was applied immediately thereafter (88% vs. 59% of control diameter, p less than 0.02), but not if blood was applied 7 days later. Studies in 16 normal CCA's established that there was a considerable margin between the laser energy required to induce dilatation and that which caused perforation, providing that the fiber remained relatively central within the artery. Morphological examination demonstrated focal loss of endothelial cells immediately after laser application, followed approximately 7 days later by the development of areas of intimal hyperplasia. Only minimal changes were observed in the medial or adventitial layers. In a second study, the basilar artery of seven dogs was constricted chronically by two intracisternal injections of autologous blood 3 days apart. Five dogs received endovascular laser treatment 7 or 10 days after the first injection, when basilar artery diameter was reduced to a mean of 61% and 77% of control, respectively. Immediately following treatment, basilar artery diameter increased to 104% and 102% of resting diameter, respectively. Both untreated and laser-treated arteries were smaller than the control diameter at 30 days (80% and 82%, respectively), but in each group the vasodilatory response to hypercapnia was preserved. These findings indicate that 1-microsecond laser pulses are well tolerated by systemic and cerebral arteries in two different animal models, and suggest that the 480-nm pulsed-dye laser may have an application for the treatment or prophylaxis of cerebral vasospasm.

Animals↗

PubMed1990

Transsphenoidal surgery for visual loss in patients with pituitary adenomas.

This paper presents the results of transsphenoidal surgery in 41 consecutive patients with visual loss from pituitary adenomas. The most common pattern of loss was bitemporal hemianopia. Transsphenoidal decompression resulted in visual improvement in 78% of patients. If patients with optic atrophy and pre-operative complete blindness were excluded, improvement extended to 94% of patients. Because of its efficacy and low morbidity, transsphenoidal resection of pituitary tumours is the procedure of choice for most adenomas with extrasellar extension and visual field loss.

Adenoma↗

PubMed1990

Cyclosporine A reduces cerebral vasospasm after subarachnoid hemorrhage in dogs.

The double subarachnoid hemorrhage canine model was used to test the prophylactic value of immunosuppression in the prevention of cerebral vasospasm after subarachnoid hemorrhage. Dogs treated with cyclosporine A following the regimen prescribed for organ transplant procedures in patients showed a significant reduction in the severity of angiographic constriction of cerebral arteries. While basilar artery diameter after double experimental subarachnoid hemorrhage in a series of untreated dogs (n = 34) averaged 65% of baseline diameter, arterial diameter in dogs treated prophylactically (n = 18) with 6 mg/kg/day cyclosporine A and adjunct low-dose steroid averaged 80% of baseline diameter, for a mean reduction in the severity of chronic arterial constriction of 42%. More important than the average effect, however, is the statistical observation that this mean improvement was obtained primarily by a dramatic reduction in the incidence of severe cerebral vasospasm, the situation most likely to account for morbidity and mortality after aneurysmal rupture.

Animals↗

PubMed1990

Clinically nonfunctioning pituitary tumors are monoclonal in origin.

Clinically nonfunctioning pituitary adenomas are benign neoplasms comprising approximately 25-30% of pituitary tumors. Little is known about the pathogenesis of pituitary neoplasia. Clonal analysis allows one to make the important distinction between a polyclonal proliferation in response to a stimulatory factor versus a monoclonal expansion of a genetically aberrant cell. We investigated the clonal origin of pituitary tumors using X-linked restriction fragment length polymorphisms at the phosphoglycerate kinase and hypoxanthine phosphoribosyl-transferase genes. Restriction enzymes were used to distinguish maternal and paternal X-chromosomes, and combined with a methylation-sensitive restriction enzyme to analyze allelic X-inactivation patterns in six pituitary adenomas. All six tumors showed a monoclonal pattern of X-inactivation. These data indicate that nonfunctioning pituitary adenomas are unicellular in origin, a result consistent with the hypothesis that this tumor type is due to somatic mutation.

Adenoma↗

PubMed1990

The importance of dopamine in the pathogenesis of experimental prolactinomas.

The factors responsible for the production of prolactin-secreting tumors are obscure. One hypothesis, that chronic loss of dopamine control from the hypothalamus may be associated with prolactinoma formation, was tested. Female adult Fischer 344 rats were subjected to ovariectomy and were then given subcutaneous implants of diethylstilbestrol (DES) Silastic capsules to produce lactotrophic hyperplasia. Sequential studies assessed the neuronal activity of the tuberoinfundibular dopaminergic neurons of the arcuate nucleus of the hypothalamus (A12) during and after this estrogen-induced pituitary growth. Immunocytochemical staining for tyrosine hydroxylase was used as a marker for dopamine synthesis, plasma radioimmunoassay provided plasma prolactin levels, and magnetic resonance imaging and histological studies were performed to examine the structural changes occurring in the pituitary gland. Animals were sacrificed from 3 to 67 days after DES implantation. To determine the reversibility of the estrogen-induced changes, rats were also sacrificed at different time intervals after the removal of 30-, 40-, or 60-day DES implants. After 30 days of DES treatment, plasma prolactin levels increased 40-fold and pituitary weight increased more than threefold. Tyrosine hydroxylase immunoreactivity diminished gradually and was almost completely depleted at 30 days. Pituitary histology revealed marked prolactin cell hyperplasia. These changes were completely reversible; removal of the capsule after 30 days resulted in eventual normalization of plasma prolactin levels and pituitary size and in restoration of tyrosine hydroxylase immunoreactivity in the A12 region. Sixty days of DES treatment produced large hemorrhagic tumors with sustained high plasma prolactin levels and an irreversibly distorted A12 area. These observations suggest that in these animals loss of dopamine regulation secondary to estrogen stimulation initially produces prolactin hyperplasia but that prolonged loss leads to adenoma formation.

Animals↗

PubMed1990

The role of inflammation in experimental cerebral vasospasm.

The short-term (less than or equal to 72-hour) cerebral vascular reaction to subarachnoid injectates of various specific blood components was determined by angiography in a canine model of cerebral vasospasm. Cell-free subarachnoid clots of autologous plasma in the basal cistern were found to produce no significant reaction of the basilar artery, while whole-blood clots induced a small (15%) chronic constriction after 24 hours. Because the plasma clots were not well retained in the basal cistern, however, small beads (dextran or latex) were added to stabilize them. Injection of beads and plasma led to moderate-to-severe chronic vasoconstriction (35% to 40%) with rapid onset. Control experiments demonstrated that these foreign bodies (beads) alone induced this vascular reaction. Histological examination showed that severe inflammation followed the introduction of subarachnoid beads. The experiments demonstrate that inflammation alone, in the absence of other processes associated with subarachnoid hemorrhage, may induce persistent and severe cerebroarterial constriction and raises the possibility that inflammation in response to subarachnoid blood may play a role in clinical vasospasm.

Animals↗

PubMed1990

Evidence of the role of hemolysis in experimental cerebral vasospasm.

The short-term (less than or equal to 72-hour) reaction to subarachnoid injections of various blood components was determined in a canine model of cerebral vasospasm. Platelet-rich plasma (PRP) formed durable clots in the basal cistern surrounding the basilar artery and provoked no vascular reaction in 72 hours or more. Freshly isolated autologous erythrocytes resuspended in PRP likewise provoked no vasoconstriction in 72 hours although a second injection of fresh erythrocytes in PRP induced significant reaction, as in the conventional "double subarachnoid hemorrhage (SAH)" canine model. Hemolysate of fresh erythrocytes led to a severe immediate vascular reaction after introduction into the basal cistern using PRP as the carrier/clotting medium, as did the injection of intact erythrocytes incubated ex vivo for 72 hours. Resolution of the initial reaction was rapid for hemolysate, but slow and (depending on hematocrit) incomplete for intact "aged" erythrocytes. In vitro measurements of erythrocyte lysis in these media and histological examination indicate that the production of erythrocyte lysate was responsible for the vascular reaction observed, suggesting that the rate of lysis of erythrocytes in the subarachnoid clot is a major factor in the genesis of vasospasm after SAH.

Animals↗

PubMed1990

Precocious puberty following head injury. Case report.

A 6-year-old girl developed secondary sexual characteristics 5 months after severe closed head injury. Endocrinological tests confirmed a pubertal sexual condition; there was also diminution of serum melatonin and disruption of the diurnal pattern. Magnetic resonance imaging demonstrated focal hypothalamic injury; this is believed to be the first time such a posttraumatic lesion has been demonstrated by imaging techniques. The pathophysiology of this condition is discussed.

Brain Stem↗

PubMed1990

Biologically inert synthetic dural substitutes. Appraisal of a medical-grade aliphatic polyurethane and a polysiloxane-carbonate block copolymer.

Two types of artificial membranes, a medical-grade aliphatic polyurethane and a polysiloxane-carbonate block copolymer, were tested as substitutes for dura in 24 and 12 rabbits, respectively. The films were placed either epidurally, subdurally, or as dural grafts in equal subgroups of animals. The postoperative course was uneventful with no manifestations of convulsive disorder or cerebrospinal fluid leak. The animals were sacrificed 3, 6, or 9 months after implantation of the artificial membranes. Both types of artificial membranes were easily removed from the underlying nervous and the other surrounding tissues. The histological examination failed to reveal adhesions, neomembrane formations, or any type of foreign body reactions to the polyurethane film. The implantation of the polysiloxane-carbonate film caused no reaction when it was applied epidurally. As a dural graft, the polysiloxane-carbonate copolymer induced the formation of a thin neomembrane of one to two layers of fibroblasts which formed a watertight seal of the dural defect. A similar thin neomembrane was found to encase this artificial membrane in the group of animals in which it was implanted subdurally. There was no foreign body reaction to the polysiloxane-carbonate film. The authors conclude that these materials hold promise as dural substitutes or in the prevention of spinal dural scarring, and should be evaluated clinically.

Animals↗

PubMed1989

Elevated serum lipids in hypogonadal men with and without hyperprolactinemia.

STUDY OBJECTIVE: To determine whether men with hypogonadism are at risk for hyperlipidemia. DESIGN: Case-control study. SETTING: Neuroendocrine clinical center of a referral-based university medical center. PATIENTS: Consecutive sample of 18 men with testosterone deficiency who had prolactin-secreting pituitary adenomas, 15 men with acquired secondary hypogonadism and normal prolactin levels, and 33 normal male controls. MEASUREMENTS AND MAIN RESULTS: We found a significant elevation in fasting cholesterol (6.23 +/- 0.28 mmol/L [mean +/- SE] compared with 5.17 +/- 0.13 mmol/L [241 +/- 11 mg/dL compared with 200 +/- 5 mg/dL], P less than 0.01), low density lipoprotein (LDL) cholesterol (4.11 +/- 0.23 mmol/L compared with 3.34 +/- 0.13 mmol/L [159 +/- 9 mg/dL compared with 129 +/- 5 mg/dL], P less than 0.05), and triglycerides (1.85 +/- 0.26 mmol/L compared with 1.11 +/- 0.07 mmol/L [164 +/- 23 mg/dL compared with 98 +/- 6 mg/dL], P less than 0.001) in men with hyperprolactinemia compared with controls. In the normoprolactinemic hypogonadal men, cholesterol (6.28 +/- 0.34 mmol/L [243 +/- 13 mg/dL], P less than 0.01), LDL cholesterol (4.34 +/- 0.34 mmol/L [168 +/- 13 mg/dL], P less than 0.01), and triglycerides (1.61 +/- 0.18 mmol/L [143 +/- 16 mg/dL], P less than 0.05) were also significantly higher than in the controls, and were the same as in the hyperprolactinemic men. High density lipoprotein (HDL) cholesterol did not differ among the three groups. CONCLUSIONS: Hypogonadism in men, with or without hyperprolactinemia, may be associated with elevation of fasting serum cholesterol, LDL cholesterol, and triglycerides compared with normal men. These data suggest that serum lipid levels should be evaluated in hypogonadal men. The presence of lipid abnormalities may affect the decision to treat testosterone deficiency in these patients.

Adolescent↗

PubMed1989

Loss of distinct regions on the short arm of chromosome 17 associated with tumorigenesis of human astrocytomas.

Astrocytomas, including glioblastoma multiforme, represent the most frequent and deadly primary neoplasms of the human nervous system. Despite a number of previous cytogenetic and oncogene studies primarily focusing on malignant astrocytomas, the primary mechanism of tumor initiation has remained obscure. The loss or inactivation of "tumor suppressor" genes are thought to play a fundamental role in the development of many human cancers. Thus, we have analyzed astrocytomas of various histological malignancy grades with polymorphic DNA markers to search for specific chromosomal deletions potentially pointing to loci containing tumor suppressor genes. Loss of constitutional heterozygosity indicating chromosomal loss or deletions was most frequently seen for markers on the short arm of chromosome 17 in 50% of the informative tumors (5 of 10 informative cases) and, to a lesser extent, for markers on chromosomes 1 and 10. Deletions on chromosome 17p were seen in both low-grade and high-grade malignant astrocytomas, suggesting that this chromosome may contain a tumor suppressor gene associated with the early events in tumorigenesis. The common region of deletions on the short arm of chromosome 17 is, therefore, clearly distinct from the gene causing von Recklinghausen neurofibromatosis (NF1), a tumor syndrome associated with glial tumors that maps to the long arm of chromosome 17. The search for progressively smaller deletions on chromosome 17p in astrocytomas may be the way to clone and characterize this locus, thus leading to insights into normal and abnormal growth and differentiation of glial cells.

Astrocytoma↗

PubMed1989

The calmodulin antagonist trifluoperazine provides mild prophylactic protection against cerebral vasospasm after subarachnoid hemorrhage, but no therapeutic value.

In vitro studies of the canine basilar artery have demonstrated that calmodulin antagonism can effectively inhibit cerebral arterial smooth muscle contractility. The prophylactic and therapeutic effectiveness of a potent calmodulin antagonist, the phenothiazine compound trifluoperazine (TFP), was investigated in vivo over a wide range of doses in the well-documented "double-subarachnoid hemorrhage" canine model of cerebral vasospasm. The compound is perhaps more well-known under its trade name, Stelazine, as a classic antipsychotic drug. The drug demonstrated no therapeutic relief of preexisting chronic cerebral vasospasm at any time during 2 days of systemic administration at any practical dose. At doses far in excess of the normally accepted therapeutic range in humans, a prophylactic regimen reduced the severity of chronic cerebral vasospasm after subarachnoid hemorrhage by approximately 35% compared to untreated dogs.

Animals↗

PubMed1989

Gonadotropin and alpha-subunit responses to chronic gonadotropin-releasing hormone analog administration in patients with glycoprotein hormone-secreting pituitary tumors.

Pituitary tumors secreting intact glycoprotein hormones (LH, FSH, and TSH) and/or alpha-subunit are being increasingly recognized. Because chronic administration of GnRH analogs decreases gonadotropin secretion in normal subjects, we investigated gonadotropin and alpha-subunit responses to chronic GnRH analog administration in five men with glycoprotein hormone-secreting pituitary tumors. Two patients (patients A and B) received the GnRH agonist analog (D-Trp6-Pro9-NEt-LHRH) for 4 weeks as a daily sc dose (8 micrograms/kg.day). In both, secretion of LH and/or alpha-subunit increased markedly. Subsequently, three patients received a higher analog dose (32 micrograms/kg.day) for a longer duration (8 weeks). One patient with a LH- and FSH-secreting tumor (patient C) had a highly significant (P less than 0.001) fall in serum LH and FSH concentrations; however, alpha-subunit secretion increased. During a subsequent study, when this patient received a lower dose (8 micrograms/kg.day) for 8 weeks, gonadotropin suppression also occurred. In two additional patients who received this dose (32 micrograms/kg.day), it had a persistent agonist effect on FSH beta (patient D) and alpha-subunit secretion (patient E). A marked increase in alpha-subunit secretion occurred in all five patients, regardless of whether basal serum alpha-subunit concentrations were elevated. These patients received the GnRH analog at doses 2-8 times greater than those that suppress gonadotropin secretion in normal men. Serum LH and FSH concentrations decreased in only one patient with a gonadotropin-secreting adenoma. The serum LH and FSH responses to acute GnRH stimulation did not predict the gonadotropin responses to chronic GnRH analog administration. Thus, gonadotropin and alpha-subunit production by most pituitary adenomas is augmented during chronic GnRH analog administration, consistent with defective GnRH desensitization in the adenomatous tissue. Despite the heterogeneous gonadotropin responses to the GnRH analog in these patients, serum alpha-subunit levels increased in all patients, indicating dissociation in the secretion of intact gonadotropins and alpha-subunit.

Adenoma↗

PubMed1989

Immunological reaction against the aging human subarachnoid erythrocyte. A model for the onset of cerebral vasospasm after subarachnoid hemorrhage.

The role of the aging human erythrocyte in the mechanisms leading to cerebral vasospasm after subarachnoid hemorrhage was investigated using an in vitro model for the environment of the erythrocyte in a subarachnoid blood clot. It has long been suspected that, due to its potent vasoactivity, erythrocyte lysate provides the major vasoconstrictive input to cerebral arteries during vasospasm. Under the model conditions (incubation at 37 degrees C in an artificial cerebrospinal fluid), however, the rate of spontaneous hemolysis was quite slow (about 1%/day), becoming only somewhat more rapid after 4 days' incubation. The rate of hemolysis of aging erythrocytes was dramatically increased (500- to 1000-fold) by the addition of plasma proteins, but only after the erythrocytes had aged 2 to 3 days, or more. The mechanism of age-dependent, plasma-induced hemolysis of originally autologous erythrocytes is shown to involve activation of the plasma complement protein pathway, analogous to the mechanisms of innate immunity which lead to lysis of nonautologous cell types and activate the inflammatory response.

Aging↗

PubMed1988

Management of large pituitary adenomas by transsphenoidal surgery.

We evaluated the ability of transsphenoidal surgery to produce visual improvement, endocrine remission, and complete tumor removal in 113 patients with pituitary adenomas extending beyond the sella turcica. Eighty-one percent of patients with preoperative visual field defects had postoperative improvement, 19% had no change, and none deteriorated significantly. Seventy-nine percent of patients with diminished preoperative visual acuity had postoperative improvement; none deteriorated. Endocrine remission of functioning tumors was achieved in 43% of patients and complete resection by computed tomography scanning was also obtained in 43%. There were no deaths in this series and the major complication was cerebrospinal fluid leak, which occurred in 3% of patients. Comparison with transfrontal surgery suggests that these results are as good as those with transfrontal procedures and that the incidence of serious side effects is considerably lower. Transsphenoidal surgery is safe and effective in the surgical management of large pituitary adenomas.

Adenoma↗

PubMed1988

Dopaminergic regulation of alpha-subunit secretion and messenger ribonucleic acid levels in alpha-secreting pituitary tumors.

Glycoprotein hormone and/or subunit secretion has been increasingly recognized in patients with pituitary nonsecretory adenomas and alpha-subunit secretion has been reported to occur in 5-10% of all pituitary tumors. We investigated the dopaminergic regulation of alpha-subunit secretion in four patients with alpha-subunit secreting pituitary adenomas documented by serum and immunocytochemical studies. In three of the four patients there was a significant decrease in serum alpha-subunit concentrations during 6 weeks of bromocriptine administration. Tumor size decreased in two patients. In pituitary tumor cells from one patient cultured in vitro, dopamine caused a highly significant decrease in media alpha-subunit concentrations. To investigate whether dopaminergic regulation of alpha-subunit secretion occurs at a pre- or posttranslational level, messenger RNA (mRNA) from cultured tumor cells from one patient was analyzed by Northern blot techniques. A decrease in alpha-subunit mRNA occurred in cells incubated with 10(-10), 10(-8), and 10(-6) M dopamine. We conclude that dopamine suppressed pituitary tumor alpha-subunit secretion and mRNA levels. Dopamine agonists may be of benefit in the therapy of patients with such tumors.

Adenoma↗